Procedures for multiple outcome measures with applications to multiple sclerosis clinical trials

In planning clinical trials in many subject areas, researchers often find it difficult to designate one single outcome measure as the primary endpoint to describe treatment efficacy. When a disease affects a patient's functions in multiple dimensions, expecting one outcome measure to assess treatment efficacy in a comprehensive way may not be realistic. Multiple sclerosis (MS) is one such complex disease. The topic addressed in this thesis concerns approaches for the design and analysis of clinical trials where a multidimensional outcome measure is used to measure treatment efficacy. The most common approach is to select a single primary endpoint for formal statistical testing with all other outcome measures considered as secondary. This thesis is concerned with the situation where agreement on a single primary endpoint is not possible so that methods based on multiple endpoints are required. Five methods, Bonferroni adjustment, Hotelling's T2, O'Brien's OLS and GLS statistics and disjunctive outcome measures are examined and compared through power and sample size calculations. Our discussion of these methods is focused on two-armed (placebo and treatment) randomized clinical trials based on continuous outcome measures. We assume that the data to be analyzed are the changes in the responses from the baseline to the end of the trial and the underlying distribution of the multiple outcome measures can be approximated as multivariate normal. Our investigation is focused on the features of the configuration of the standardized differences in the underlying population means and the correlation structure among the multiple outcome measures. Specifically, several special cases are examined to highlight the main differences among the statistical properties of these methods. We also apply the methods considered to two MS clinical trial data sets for a more focused comparison of these methods for actual MS patient populations.Science, Faculty ofStatistics, Department ofGraduat

The SALOME study: recruitment experiences in a clinical trial offering injectable diacetylmorphine and hydromorphone for opioid dependency

Background. The Study to Assess Long-term Opioid Medication Effectiveness (SALOME) is a two-stage phase III, single site (Vancouver, Canada), randomized, double blind controlled trial designed to test if hydromorphone is as effective as diacetylmorphine for the treatment of long-term illicit opioid injection. Recruiting participants for clinical trials continues to be a challenge in medical and addiction research, with many studies not being able to reach the planned sample size in a timely manner. The aim of this study is to describe the recruitment strategies in SALOME, which offered appealing treatments but had limited clinic capacity and no guaranteed post-trial continuation of the treatments. Methods SALOME included chronic opioid-dependent, current illicit injection opioid users who had at least one previous episode of opioid maintenance treatment. Regulatory approvals were received in June 2011 and recruitment strategies were implemented over the next 5 months. Recruitment strategies included ongoing open communication with the community, a consistent and accessible team and participant-centered screening. All applicants completed a pre-screening checklist to assess prerequisites. Applicants meeting these prerequisites were later contacted to commence the screening process. Results A total of 598 applications were received over the two-year recruitment period; 130 were received on the first day of recruitment. Of these applicants, 485 met prerequisites; however, many could not be found or were not reached before recruitment ended. For the 253 candidates who initiated the screening process, the average time lapse between application and screening date was 8.3 months (standard deviation [SD] = 4.44) and for the 202 randomized to the study, the average processing time from initial screen to randomization was 25.9 days (SD = 37.48; Median = 15.0). Conclusions As in prior trials offering injectable diacetylmorphine within a supervised model, recruiting participants for this study took longer than planned. The recruitment challenges overcome in SALOME were due to the high number of applicants compared with the limited number that could be randomized and treated. Our study emphasizes the value of integrating these strategies into clinical addiction research to overcome study-specific barriers. Trial registration ClinicalTrials.gov: NCT01447212 .Population and Public Health (SPPH), School ofNon UBCMedicine, Faculty ofReviewedFacult

Adherence to Antitumor Necrosis Factor Use Recommendations in Spondyloarthritis: Measurement and Effect in the DESIR Cohort

International audienc

Client satisfaction among participants in a randomized trial comparing oral methadone and injectable diacetylmorphine for long-term opioid-dependency

Background: Substitution with opioid-agonists (e.g., methadone) has shown to be an effective treatment for chronic long-term opioid dependency. Patient satisfaction with treatment has been associated with improved addiction treatment outcomes. However, there is a paucity of studies evaluating patients' satisfaction with Opioid Substitution Treatment (OST). In the present study, participants' satisfaction with OST was evaluated at 3 and 12 months. We sought to test the relationship between satisfaction and patients' characteristics, the treatment modality received and treatment outcomes. Methods Data from a randomized controlled trial, the North American Opiate Medication Initiative (NAOMI), conducted in Vancouver and Montreal (Canada) between 2005-2008, was analyzed. The NAOMI study compared the effectiveness of oral methadone vs. injectable diacetylmorphine over 12 months. A small sub-group of patients received injectable hydromorphone on a double blind basis with diacetylmorphine. The Client Satisfaction Questionnaire (CSQ-8) was used to measure satisfaction with treatment. CSQ-8 scores, as well as retention and response to treatment, did not differ between those receiving hydromorphone and diacetylmorphine at 3 or 12 months assessments; therefore, these two groups were analyzed together as the 'injectable' treatment group. Results A total of 232 (92%) and 237 (94%) participants completed the CSQ-8 at 3 and 12 months, respectively. Participants in both groups were highly satisfied with treatment. Independent of treatment group, participants satisfied with treatment at 3 months were more likely to be retained at 12 months. Multivariate analysis indicated that satisfaction was greater among those randomized to the injection group after controlling for treatment effectiveness. Participants who were retained, responded to treatment, and had fewer psychological symptoms were more satisfied with treatment. Finally, open-ended comments were made by 149 (60.3%) participants; concerns about the randomization process and the study ending were most commonly reported by participants receiving the oral and injectable medications, respectively. Conclusions The higher satisfaction among those receiving medically prescribed injectable diacetylmorphine (or hydromorphone) supports current evidence regarding the attractiveness of this treatment for long-term, opioid-dependent individuals not benefiting sufficiently from other treatments. In addition, the measurement of treatment satisfaction provides valuable information about participants at risk of relapse and in need of additional services. Trial Registration ClinicalTrials.gov Identifier: NCT00175357Population and Public Health (SPPH), School ofNon UBCMedicine, Faculty ofReviewedFacult

Sex work involvement among women with long-term opioid injection drug dependence who enter opioid agonist treatment

Background: Substitution with opioid-agonists (e.g., methadone) has shown to be an effective treatment for chronic long-term opioid dependency. Survival sex work, very common among injection drug users, has been associated with poor Opioid Agonist Treatment (OAT) engagement, retention and response. Therefore, this study was undertaken to determine factors associated with engaging in sex work among long-term opioid dependent women receiving OAT. Methods Data from a randomized controlled trial, the North American Opiate Medication Initiative (NAOMI), conducted in Vancouver and Montreal (Canada) between 2005-2008, was analyzed. The NAOMI study compared the effectiveness of oral methadone to injectable diacetylmorphine or injectable hydromorphone, the last two on a double blind basis, over 12 months. A research team, independent of the clinic services, obtained outcome evaluations at baseline and follow-up (3, 6, 9, 12, 18 and 24 months). Results A total 53.6% of women reported engaging in sex work in at least one of the research visits. At treatment initiation, women who were younger and had fewer years of education were more likely to be engaged in sex work. The multivariate logistic generalized estimating equation regression analysis determined that psychological symptoms, and high illicit heroin and cocaine use correlated with women's involvement in sex work during the study period. Conclusions After entering OAT, women using injection drugs and engaging in sex work represent a particularly vulnerable group showing poorer psychological health and a higher use of heroin and cocaine compared to women not engaging in sex work. These factors must be taken into consideration in the planning and provision of OAT in order to improve treatment outcomes. Trial Registration NCT00175357.Population and Public Health (SPPH), School ofNon UBCMedicine, Faculty ofReviewedFacult

Long-Term (10-Year) Mortality of Younger Previously Healthy Patients With Severe Sepsis/Septic Shock Is Worse Than That of Patients With Nonseptic Critical Illness and of General Population.

Long-term (1- to 10-year) outcomes after severe sepsis in previously healthy persons are unknown. We aimed to determine the 1- to 10-year mortality rates of previously healthy patients with severe sepsis and compare these to mortality rates of patients with nonseptic critical illness and the general population

Costs of early spondyloarthritis: estimates from the first 3 years of the DESIR cohort

International audienceObjectives: To value health resource utilisation and productivity losses in DESIR, a longitudinal French cohort of 708 patients with early spondyloarthritis (SpA) enrolled between 2007 and 2010, and identify factors associated with costs in the first 3 years of follow-up. Methods: Self-reported clinical data from DESIR and French public data were used to value health resource utilisation and productivity losses in 2013 Euros. Factors associated with costs, including and excluding biological drugs, were identified in generalised linear models using the generalised estimating equations algorithm to account for repeated observations over participants. Results: The mean (±SD) annual cost per patient was €5004±6870 in year 1, decreasing to €4961±7457 in year 3. Patients who never received a biologic had mean 3-year total costs of €4789±6022 compared to €38 206±19 829 among those who received a biologic. Factors associated with increased total costs were peripheral arthritis (rate ratio (RR) 1.19; 95% CI 1.04 to 1.37; p<0.0001), time on biologics (RR 1.23 per month; 1.21, 1.24; p<0.0001), and average BASFI score (RR 1.18/10 point increase; 1.15, 1.25; p<0.0001). Factors associated with increased costs excluding biologics were baseline age (RR 1.10 per 5 year increase; 1.05, 1.16; p<0.0001), peripheral arthritis (RR 1.20; 1.02, 1.40; p<0.0133), time on biologics (RR 1.04 per month; 1.02, 1.05; p<0.0001), and average BASDAI score (RR 1.21 per 10 point increase; 1.16, 1.25; p<0.0001). Conclusions: In addition to biologics, factors like age, peripheral arthritis and disease activity independently increase SpA-related costs. This study may serve as a benchmark for cost of illness among patients with early SpA in the biologic era